The details of what is described as a profoundly unethical marketing ploy masquerading as a phase IV trial of gabapentin were reported June 27 in the Archives of Internal Medicine.
The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a so-called seeding trial, in which the stated objective was to assess the safety and efficacy of gabapentin, but the actual aim was to increase prescribing of the drug by duping the very physicians recruited to conduct the "trial," according to three medicolegal consultants involved in litigation against the drug’s manufacturer.
"Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of phase IV postmarketing clinical trials," wrote Samuel D. Krumholz, Dr. David S. Egilman, and Dr. Joseph S. Ross.
"Our analysis is only the second comprehensive account of a seeding trial based on primary source documents, and [it] clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study," they noted.
Mr. Krumholz and Dr. Egilman are with Never Again Consulting, an independent Massachusetts firm that conducts research and analysis in support of occupational and environmental health. Dr. Egilman is also in the department of community health at Brown University, Providence, R.I., and Dr. Ross is at Yale–New Haven (Conn.) Hospital Center for Outcomes Research and Evaluation.
Their access to a complete set of documents and depositions produced during litigation against Parke-Davis (now a subsidiary of Pfizer) enabled them to analyze and expose seeding trials, which are "used to promote drugs recently approved or under review by the U.S. Food and Drug Administration by encouraging prescribers to use these medications under the guise of participating as an investigator in [the] trial."
The STEPS trial included the three key traits said to characterize seeding trials: involvement of the marketing department in study conception and design; involvement of the marketing department in data collection and analysis; and nondisclosure of the study’s true purpose from physicians, patients, and institutional review boards.
When asked to comment on the report, Pfizer spokesperson Christopher Loder wrote in an e-mail that "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than 2 decades and there is an extensive body of publicly available literature on its safety and its use."
In the STEPS trial, Parke-Davis recruited 772 physicians to prescribe Neurontin (gabapentin) and titrate the dose upward in patients whose partial seizures were not completely controlled by other drugs. The drug company purposefully recruited "site investigators with little or no clinical trial experience [and] provided insufficient training," and limited enrollment to about four patients per investigator.
The study design was uncontrolled and unblinded, and its rigid titration protocol led to the exclusion of 87% of the study subjects. One institutional review board that twice rejected the STEPS application to be conducted at their medical center stated that "the entry criteria and outcome measures are too vague to allow any scientific conclusions to be reach[ed]."
Parke-Davis sales representatives collected and recorded individual subject data. In a clear example of data tampering, they not only attended epilepsy patients’ office visits (under the guise of "shadowing" the clinician), but also actively promoted the use of Neurontin and blocked the use of competing medications, particularly lamotrigine (Lamictal), at those visits. They also rewarded participating investigators with free lunches and dinners.
Without informing either patients or physicians, the drug company’s marketing department monitored each investigator’s prescribing practices. It documented a 38% increase in prescriptions of Neurontin after investigators attended an introductory briefing, as well as a 10% increase in the average prescribed dose. It also compared prescribing patterns between study investigators and a control group of nonparticipating neurologists, and documented increased prescribing of Neurontin only among the study participants.
In numerous internal documents, Parke-Davis described STEPS as a marketing strategy rather than a scientific study. The actual findings of the trial were immaterial; the strategy’s success in increasing market share in new prescriptions was paramount, the authors said (Arch. Intern. Med. 2011;171:1100-7).
"Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB [institutional review board] system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry," they added.